Rapamycin 42-ester of 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) is an ester of rapamycin, commercially known as Temsirolimus, which has demonstrated significant inhibitory effects on tumor growth both in vitro and in vivo models including humans. CCI-779 may delay the time to progression of tumors or time to tumor recurrence, which is more typical of cytostatic rather than cytotoxic agents. CCI-779 is considered to have a mechanism of action that is similar to that of sirolimus.

The preparation and use of hydroxyesters of rapamycin, including CCI-779, are disclosed in U.S. Pat. No. 5,362,718. CCI-779 can be synthesized by the non-regioselective acylation of rapamycin, as described in Example 10 of the U.S. Pat. No. 5,362,718. The synthesis, however, is complicated due to the presence of mixtures of the desired 42-ester, with 31-esterified rapamycin, as well as 31, 42-diesterified rapamycin and unreacted rapamycin. In an effort to consume the remaining starting rapamycin, the reaction was allowed to proceed for a longer period with negative consequences, the quantity of the 31, 42-bisester increased significantly. The resulting crude product [I] is contaminated with unreacted rapamycin and 31, 42-bisester, and subsequent column chromatography purification effort has proved to be difficult because of a very close retention time with product [I]. Overall, the major obstacle in large-scale production of compound [I] as per the process of the above patent appears to be the non-regiospecificity that is further complicated by purification difficulties, due to similarity of functional groups.
CCI-779 can also be prepared by the acylation of the 31-silyl ether of rapamycin with a ketal of bis-(hydroxymethyl)propionic acid, followed by removal of the 31-silyl ether and ketal protecting group from the bis-(hydroxymethyl)propionic acid, as described in U.S. Pat. No. 6,277,983. However, the crude 42-monoester produced from this regioselective synthesis requires further purification by column chromatography to remove residual amounts of diester by-products and unreacted rapamycin starting material.
International (PCT) Publication No. WO 2005016935 discloses a process for the preparation of 42-ester of rapamycin using boronic acid chemistry. The process involves acylating a rapamycine 31-silyl ether; selective hydrolysis of the 42-ester boronate 31-silyl ether; and treating the rapamycine 42-ester boronate with a suitable diol.
U.S. Publication No. 2005234086 describes synthesis of CCI-779 using enzyme Lipase as a catalyst but there are several disadvantages of the use of enzymatic catalysis on an industrial scale, for instance in terms of volume, work-up and overall cost.
U.S. Publication No. 20070129395 describes synthesis of purified crystalline CCI-779. The specification also discloses purified crystalline CCI-779 having a DSC thermogram having an endotherm peak greater than about 165° C. and an XRD peak pattern having peaks at 2 theta of about 7.7, 9.0, 11.4, 12.6, 13.3, 15.0, 15.4, 16.2, 66.5, 34.8, 43.7, 31.4 and 58.
Several of the above processes either have a problem of low yield and purity or are difficult to carry out on a commercial scale and are expensive. Therefore, there is a need to provide a process for the preparation of a compound of Formula (I), which is regio-selective, cost effective, scalable, and industrially applicable. The present invention provides a process, which is efficient, cost effective and does not result in impure product, thus making the process amenable for commercial scale use.